JPWO2013061919A1 - Novel compound and process for producing the same - Google Patents

Novel compound and process for producing the same Download PDF

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JPWO2013061919A1
JPWO2013061919A1 JP2013540765A JP2013540765A JPWO2013061919A1 JP WO2013061919 A1 JPWO2013061919 A1 JP WO2013061919A1 JP 2013540765 A JP2013540765 A JP 2013540765A JP 2013540765 A JP2013540765 A JP 2013540765A JP WO2013061919 A1 JPWO2013061919 A1 JP WO2013061919A1
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信孝 今村
信孝 今村
中川 和也
和也 中川
真治 徳山
真治 徳山
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Shizuoka University NUC
Ritsumeikan Trust
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Abstract

本発明の課題は、抗カビ物質として有用な新規化合物及びその製造法を提供することである。本発明は、式(I):

Figure 2013061919

(式中、Rは、

Figure 2013061919

を示し、Rは、

Figure 2013061919

を示す。)で表される化合物又はその塩、及び微生物を用いる該化合物の製造方法に関する。An object of the present invention is to provide a novel compound useful as an antifungal substance and a method for producing the same. The present invention relates to a compound of formula (I 0 ):

Figure 2013061919

(Wherein R 1 is

Figure 2013061919

R 2 is

Figure 2013061919

Indicates. Or a salt thereof, and a method for producing the compound using a microorganism.

Description

本発明は、抗カビ物質として有用な新規化合物、および微生物を用いたその製造法に関する。   The present invention relates to a novel compound useful as an antifungal substance and a method for producing the same using a microorganism.

古くから、淡水魚、例えばニジマス等の養殖場において、ミズカビ病といわれる魚病が問題となっている。ミズカビ病は、卵菌網(Oomycetes)、ミズカビ目(Saprolegniales)、ミズカビ科(Saprolegniaceae)のミズカビ属(Saprolegnia)、ワタカビ属(Achlya)、アファノマイセス属(Aphanomyces)の種によって引き起こされる。卵菌網は、近年の分子解析および生化学的な研究により、原生生物界の不等毛類に分類され、菌類様の外見を持ち(非特許文献1)、植物病原菌のPhytophthora属もこのグループに属している。   For a long time, freshwater fish, such as rainbow trout, have been a problem of fish disease called scab mold disease. Sphagnum disease is caused by species of Oomycetes, Saprolegniales, Saprolegniaceae, Saprolegnia, Achlya, and Aphanomyces. Oomyces are classified as protozoan irregular hairs by recent molecular analysis and biochemical research, and have a fungal-like appearance (Non-patent Document 1). Phytophthora genus of plant pathogens also belongs to this group. Belongs to.

従来、色素剤のマラカイトグリーンがミズカビ病の起因生物に低濃度で活性を示し(非特許文献2)、また、安価であることから予防・治療剤として使用されてきた。しかし、近年、その発がん性が懸念され、養殖食用魚への使用が禁止された。これの代替品となる養殖魚又は魚卵のミズカビ病防止薬剤として、例えば、オゾン(特許文献1)、電解水(特許文献2)、有機酸(特許文献3)及びバチルス・ズブチリス菌(特許文献4)が提案されている。また、合成抗菌保存剤のブロノポール(C3H6BrNO4)を有効成分とする薬剤(商品名「パイセス」、ノバルティスアニマルヘルス株式会社製)などが販売されている。しかし、「パイセス」はマラカイトグリーンと比べて高価であり、また、有効成分であるブロノポールには食用カキ(EC50 0.77mg/L)、魚類の餌として有用なミジンコ(EC50 1.4mg/L)、緑藻(EC50 0.0537mg/L)などの水棲生物に強い毒性が認められているため(非特許文献3)、廃棄する際に大量の水での希釈を必要とする等の問題がある。よって、より安全で効果の高い抗カビ剤の開発が望まれている。Conventionally, the coloring agent malachite green is active at low concentrations in organisms causing scab mold (Non-patent Document 2) and has been used as a preventive / therapeutic agent because it is inexpensive. However, in recent years, carcinogenicity has been a concern, and its use in farmed fish has been banned. As an alternative to this, as an aquatic agent for cultured fish or fish eggs, for example, ozone (patent document 1), electrolyzed water (patent document 2), organic acid (patent document 3), and Bacillus subtilis (patent document) 4) has been proposed. In addition, drugs containing the synthetic antibacterial preservative bronopol (C 3 H 6 BrNO 4 ) as an active ingredient (trade name “Piesse”, manufactured by Novartis Animal Health Co., Ltd.) are on the market. However, “Piesces” is more expensive than malachite green, and bronopol, an active ingredient, is an edible oyster (EC 50 0.77 mg / L) and daphnia (EC 50 1.4 mg / L) useful as fish food. In addition, since strong toxicity to aquatic organisms such as green algae (EC 50 0.0537 mg / L) is recognized (Non-patent Document 3), there is a problem that dilution with a large amount of water is required when discarding. Therefore, development of a safer and more effective antifungal agent is desired.

特開平05−236843号公報Japanese Patent Laid-Open No. 05-236843 特開平11−266733号公報JP-A-11-266733 特開2007−254463号公報JP 2007-254463 A 国際公開第2006/101060号パンフレットInternational Publication No. 2006/101060 Pamphlet

千原光雄、藻類の多様性と系統、裳華房 (1999)Mitsuo Chihara, Diversity and strains of algae, Hanafusa (1999) 江草周三、魚介類の感染症・寄生虫病、恒星社厚生閣 (2004)Shuzo Egusa, Infectious and parasitic diseases of seafood, Hoshiseisha Koseikaku (2004) マテリアル・セイフティー・データ・シート プロダクト・コード:#0585 (2007)Material Safety Data Sheet Product Code: # 0585 (2007)

上記事情に鑑み、本発明は、新規な抗カビ物質を天然界から検索し、その新規物質およびその製造法を提供することを目的とする。   In view of the above circumstances, an object of the present invention is to search for a novel antifungal substance from the natural world, and provide the novel substance and a production method thereof.

本発明者らは、上記課題を解決するために検討を重ねた結果、ストレプトマイセス属に属する微生物の培養液から得られた化合物が、選択的な抗カビ物質であることを見出し、本発明を完成するに至った。すなわち本発明は以下の発明を包含する。
(1)式(I):
As a result of repeated studies to solve the above problems, the present inventors have found that a compound obtained from a culture solution of a microorganism belonging to the genus Streptomyces is a selective antifungal substance, and the present invention. It came to complete. That is, the present invention includes the following inventions.
(1) Formula (I 0 ):

Figure 2013061919
Figure 2013061919

(式中、Rは、(Wherein R 1 is

Figure 2013061919
Figure 2013061919

を示し、Rは、R 2 is

Figure 2013061919
Figure 2013061919

を示す。)で表される化合物又はその塩。
(2)式(I):
Indicates. Or a salt thereof.
(2) Formula (I):

Figure 2013061919
Figure 2013061919

(式中、Rは、 (Wherein R is

Figure 2013061919
Figure 2013061919

又は Or

Figure 2013061919
Figure 2013061919

を示す。)で表される化合物又はその塩。
(3)(1)又は(2)に記載の化合物を生産する能力を有するストレプトマイセス属に属する微生物を培地に培養し、培養物中に該化合物を生成蓄積させ、該化合物を採取することを特徴とする(1)又は(2)に記載の化合物の製造法。
(4)(1)又は(2)に記載の化合物を有効成分として含む抗カビ剤。
Indicates. Or a salt thereof.
(3) culturing a microorganism belonging to the genus Streptomyces having the ability to produce the compound according to (1) or (2) in a medium, producing and accumulating the compound in the culture, and collecting the compound (1) The manufacturing method of the compound as described in (2) characterized by these.
(4) An antifungal agent comprising the compound according to (1) or (2) as an active ingredient.

本発明は、新規な抗カビ物質及び該物質の微生物を用いた製造法を提供する。本発明の化合物は、非常に高い抗カビ活性を有し、さらに生態系への影響が低い。よって、抗カビ剤、具体的には、魚病の予防又は治療剤、または卵菌類を起因生物とする植物疫病の防除剤成分として有用である。   The present invention provides a novel antifungal substance and a method for producing the substance using microorganisms. The compounds of the present invention have a very high antifungal activity and have a low impact on the ecosystem. Therefore, it is useful as an antifungal agent, specifically, a preventive or therapeutic agent for fish diseases, or a plant pesticidal agent component caused by oomycetes.

以下に本発明を詳細に説明する。   The present invention is described in detail below.

本発明の化合物は、放線菌(ストレプトマイセス・スピーシーズTK08046株等)から単離・精製された化合物であり、抗カビ活性を有するものである。本発明の化合物の性質及びその製造方法について以下に詳述する。   The compound of the present invention is a compound isolated and purified from actinomycetes (Streptomyces sp. TK08046 strain and the like) and has antifungal activity. The properties of the compound of the present invention and the production method thereof will be described in detail below.

1.本発明の化合物の性質
本発明の化合物は、式(I):
1. Properties of the compounds of the invention The compounds of the invention have the formula (I 0 ):

Figure 2013061919
Figure 2013061919

(式中、Rは、(Wherein R 1 is

Figure 2013061919
Figure 2013061919

を示し、Rは、R 2 is

Figure 2013061919
Figure 2013061919

を示す。)で表される化合物又はその塩(以下、「式(I)の化合物」という場合もある)である。Indicates. ) Or a salt thereof (hereinafter sometimes referred to as “compound of formula (I 0 )”).

式(I)の化合物は、式(I):Compounds of formula (I 0) of the formula (I 0):

Figure 2013061919
Figure 2013061919

において、Rが、R 1 is

Figure 2013061919
Figure 2013061919

であり、Rが、And R 2 is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−A)」という場合もある)、
が、
A compound (hereinafter sometimes referred to as “compound (I 0 -A)”),
R 1 is

Figure 2013061919
Figure 2013061919

であり、Rが、And R 2 is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−B)」という場合もある)、
が、
A compound (hereinafter sometimes referred to as “compound (I 0 -B)”),
R 1 is

Figure 2013061919
Figure 2013061919

であり、Rが、And R 2 is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−C)」という場合もある)、
が、
A compound (hereinafter sometimes referred to as “compound (I 0 -C)”),
R 1 is

Figure 2013061919
Figure 2013061919

であり、Rが、And R 2 is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−D)」という場合もある)、及び
が、
A compound (hereinafter sometimes referred to as “compound (I 0 -D)”), and R 1 is

Figure 2013061919
Figure 2013061919

であり、Rが、And R 2 is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−E)」という場合もある)からなる群から選択される少なくとも1種の化合物を含む。And at least one compound selected from the group consisting of compounds (hereinafter sometimes referred to as “compound (I 0 -E)”).

式(I)の化合物の中で、式(I):Among the compounds of formula (I 0 ), formula (I):

Figure 2013061919
Figure 2013061919

(式中、Rは、 (Wherein R is

Figure 2013061919
Figure 2013061919

又は Or

Figure 2013061919
Figure 2013061919

を示す。)で表される化合物(以下、「式(I)の化合物」という場合もある)が好ましい。 Indicates. ) (Hereinafter also referred to as “compound of formula (I)”).

式(I)の化合物は、式(I):   The compound of formula (I) is represented by formula (I):

Figure 2013061919
Figure 2013061919

において、Rが、 R is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−1)」という場合もある)、及び/又は、Rが、 A compound (hereinafter sometimes referred to as “compound (I-1)”) and / or R is

Figure 2013061919
Figure 2013061919

である化合物(以下、「化合物(I−2)」という場合もある)を含む。ここで、化合物(I−1)は上述した化合物(I−A)に相当し、化合物(I−2)は上述した化合物(I−E)に相当している。(Hereinafter also referred to as “compound (I-2)”). Here, the compound (I-1) corresponds to the compound (I 0 -A) described above, and the compound (I-2) corresponds to the compound (I 0 -E) described above.

なお、化合物(I−A)〜(I−E)は、従来の方法に従って塩(特に塩基付加塩)を形成することができる。形成された化合物の塩も、本願発明に含まれる。Compounds (I 0 -A) to (I 0 -E) can form salts (particularly base addition salts) according to conventional methods. Salts of the formed compounds are also included in the present invention.

化合物(I−A)〜(I−E)の塩基付加塩としては無機塩基又は有機塩基との塩が挙げられる。無機塩基との塩として、例えば、アンモニウム塩、アルカリ及びアルカリ土類金属塩、例えばリチウム、ナトリウム、カリウム、マグネシウム、カルシウム塩等が挙げられる、有機塩基との塩として、例えば、第1級、第2級及び第3級脂肪族及び芳香族アミン(例えば、メチルアミン、エチルアミン、プロピルアミン、イソプロピルアミン、4種のブチルアミン異性体、ジメチルアミン、ジエチルアミン、ジエタノールアミン、ジプロピルアミン、ジイソプロピルアミン、ジ−n−ブチルアミン、ピロリジン、ピペリジン、モルホリン、トリメチルアミン、トリエチルアミン、トリプロピルアミン、キヌクリジン、ピリジン、キノリン及びイソキノリン、ベンザチン、N−メチル−D−グルカミン、2−アミノ−2−(ヒドロキシメチル)−1,3−プロパンジオール、ヒドラバミン)との塩、ならびに例えばアルギニン、リシンなどのようなアミノ酸との塩が挙げられる。Examples of the base addition salt of compounds (I 0 -A) to (I 0 -E) include salts with inorganic bases or organic bases. Examples of salts with inorganic bases include ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium salts. Examples of salts with organic bases include primary, Secondary and tertiary aliphatic and aromatic amines (eg methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n -Butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) 1,3-propanediol, salts with hydrabamine) as well as, for example arginine, salts with amino acids such as lysine.

本発明の化合物(I−A)〜(I−E)又はそれらの塩は溶媒和物としても提供され得る。溶媒和物として、例えば、水和物、アルコール(例えば、メタノール、エタノール等)和物等が挙げられる。The compounds (I 0 -A) to (I 0 -E) or salts thereof of the present invention can also be provided as solvates. Examples of solvates include hydrates, alcohols (eg, methanol, ethanol, etc.) solvates, and the like.

上記化合物(I−A)(化合物(I−1))の構造式及び理化学的性質は以下のとおりである:
(1)物質の色 :赤色
(2)分子量 :706
(3)分子式 :C37H38O14
(4)質量分析 :ESI-MS(negative mode) 実測値 705.2
(5)紫外線吸収スペクトル(アセトニトリル中) λmax 217, 317, 424nm
(6)H NMR(重クロロホルム中で測定、600MHz)
δppm 12.30 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.84 (dd, J = 3.4, 10.3 Hz, 1H), 6.67 (dd, J = 3.4, 10.3 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 6.14 (d, J = 10.3 Hz, 1H), 6.06 (d, J = 9.6 Hz, 1H), 5.57 (d, J = 3.4 Hz, 1H), 5.37 (d, J = 3.4 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.75 (q, J = 6.2 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.67 (brs, 1H), 4.28 (brs, 1H), 3.90 (m, 1H), 3.62 (s, 1H), 3.56 (m, 1H), 3.23 (m, 1H), 3.20 (m, 1H), 2.55 (m, 1H), 2.54 (m, 1H), 2.45 (dd, J= 2.6, 15.8 Hz, 1H), 1.81 (d, J = 15.8 Hz, 1H), 1.47 (s, 3H), 1.44 (d, J= 3.4 Hz, 3H), 1.43 (d, J = 4.1 Hz, 3H), 1.39 (d, J = 6.2Hz, 3H), 1.36 (m, 1H)
(7)13C NMR(重クロロホルム中で測定、125MHz)
δppm 204.2, 196.8, 195.3, 188.1, 182.2, 158.1, 145.3, 142.8, 142.2, 138.8, 138.5, 138.4, 133.7, 130.5, 127.8, 127.4, 119.8, 117.4, 114.0, 95.2, 89.4, 88.8, 82.8, 79.4, 77.0, 74.4, 71.6, 71.3, 71.1, 70.7, 50.2, 42.7, 38.9, 26.5, 18.4, 15.2, 15.1
(8)溶解性 :メタノール、ジメチルスルホキシド(DMSO)、クロロホルムに可溶。水に難溶。
The structural formula and physicochemical properties of the compound (I 0 -A) (compound (I-1)) are as follows:
(1) Material color: Red (2) Molecular weight: 706
(3) Molecular formula: C 37 H 38 O 14
(4) Mass spectrometry: ESI-MS (negative mode) measured value 705.2
(5) UV absorption spectrum (in acetonitrile) λmax 217, 317, 424nm
(6) 1 H NMR (measured in deuterated chloroform, 600 MHz)
δppm 12.30 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.84 (dd, J = 3.4, 10.3 Hz, 1H), 6.67 (dd, J = 3.4, 10.3 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 6.14 (d, J = 10.3 Hz, 1H), 6.06 (d, J = 9.6 Hz, 1H), 5.57 (d, J = 3.4 Hz, 1H), 5.37 (d, J = 3.4 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.75 (q, J = 6.2 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.67 (brs, 1H), 4.28 (brs, 1H), 3.90 (m, 1H), 3.62 (s, 1H), 3.56 (m, 1H), 3.23 (m, 1H), 3.20 (m, 1H), 2.55 (m, 1H), 2.54 (m, 1H), 2.45 (dd, J = 2.6, 15.8 Hz, 1H), 1.81 (d, J = 15.8 Hz, 1H), 1.47 (s, 3H), 1.44 (d, J = 3.4 Hz, 3H), 1.43 (d, J = 4.1 Hz, 3H), 1.39 (d, J = 6.2Hz, 3H), 1.36 (m, 1H)
(7) 13 C NMR (measured in deuterated chloroform, 125 MHz)
δppm 204.2, 196.8, 195.3, 188.1, 182.2, 158.1, 145.3, 142.8, 142.2, 138.8, 138.5, 138.4, 133.7, 130.5, 127.8, 127.4, 119.8, 117.4, 114.0, 95.2, 89.4, 88.8, 82.8, 79.4, 77.0 , 74.4, 71.6, 71.3, 71.1, 70.7, 50.2, 42.7, 38.9, 26.5, 18.4, 15.2, 15.1
(8) Solubility: Soluble in methanol, dimethyl sulfoxide (DMSO) and chloroform. Insoluble in water.

化合物(I−B)の構造式及び理化学的性質は以下のとおりである:
(1)物質の色 :赤色
(2)分子量 :708
(3)分子式 :C37H40O14
(4)質量分析 :ESI-MS(negative mode) 実測値 707.2
(5)紫外線吸収スペクトル(アセトニトリル中) λmax 218, 315, 423nm
(6)H NMR(重クロロホルム中で測定、600MHz)
δppm 12.28 (brs, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 5.40 (t, J = 6.2 Hz, 1H), 5.17 (d, J = 3.4 Hz, 1H), 4.95 (dd, J = 1.4, 11.3 Hz, 1H), 4.71 (q, J = 6.8 Hz, 1H), 4.58 (brs, 1H), 4.51 (q, J = 6.9 Hz, 1H), 4.33 (m, 1H), 3.96 (brs, 1H), 3.80 (m, 1H), 3.56 (m, 1H), 3.48 (t, J = 4.1 Hz, 1H), 3.28 (dd, J = 3.4, 13.1 Hz, 1H), 2.62-2.66 (m, 2H), 2.51 (d, J = 13.1 Hz, 1H), 2.43 (ddd, J = 2.1, 4.8, 13.1 Hz, 1H ), 2.38-2.40 (m, 2H), 2.35 (dd, J = 3.4, 15.4 Hz, 1H), 2.30 (m, 1H), 2.16 (d, J = 3.4 Hz, 1H), 1.79 (d, J = 15.1 Hz, 1H), 1.45 (s, 3H), 1.40 (m, 1H), 1.39 (d, J = 6.2 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.37 (d, J = 6.9 Hz, 3H)
(7)13C NMR(重クロロホルム中で測定、125MHz)
δppm 211.0, 208.0, 204.5, 188.2, 182.3, 158.5, 145.3, 139.3, 139.1, 138.5, 133.7, 130.6, 119.8, 117.4, 114.6, 92.8, 91.4, 82.5, 79.9, 77.8, 77.4, 77.1, 74.6, 74.5, 71.5, 71.2, 71.0, 50.5, 44.1, 40.0, 36.7, 33.4, 28.3, 25.8, 17.5, 16.9, 14.8
(8)溶解性 :メタノール、ジメチルスルホキシド(DMSO)、クロロホルムに可溶。水に難溶。
The structural formula and physicochemical properties of the compound (I 0 -B) are as follows:
(1) Material color: Red (2) Molecular weight: 708
(3) Molecular formula: C 37 H 40 O 14
(4) Mass spectrometry: ESI-MS (negative mode) measured value 707.2
(5) UV absorption spectrum (in acetonitrile) λmax 218, 315, 423nm
(6) 1 H NMR (measured in deuterated chloroform, 600 MHz)
δppm 12.28 (brs, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 5.40 (t, J = 6.2 Hz, 1H), 5.17 (d, J = 3.4 Hz, 1H), 4.95 (dd, J = 1.4, 11.3 Hz, 1H), 4.71 (q, J = 6.8 Hz, 1H), 4.58 (brs, 1H), 4.51 (q, J = 6.9 Hz, 1H), 4.33 (m, 1H), 3.96 (brs, 1H), 3.80 (m, 1H), 3.56 (m, 1H), 3.48 (t, J = 4.1 Hz, 1H), 3.28 (dd, J = 3.4, 13.1 Hz, 1H), 2.62-2.66 (m, 2H), 2.51 (d, J = 13.1 Hz, 1H), 2.43 (ddd, J = 2.1, 4.8, 13.1 Hz, 1H), 2.38-2.40 (m, 2H), 2.35 (dd, J = 3.4, 15.4 Hz, 1H), 2.30 (m, 1H), 2.16 (d, J = 3.4 Hz, 1H), 1.79 (d, J = 15.1 Hz, 1H), 1.45 (s, 3H), 1.40 (m, 1H), 1.39 (d, J = 6.2 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.37 (d, J = 6.9 Hz, 3H)
(7) 13 C NMR (measured in deuterated chloroform, 125 MHz)
δppm 211.0, 208.0, 204.5, 188.2, 182.3, 158.5, 145.3, 139.3, 139.1, 138.5, 133.7, 130.6, 119.8, 117.4, 114.6, 92.8, 91.4, 82.5, 79.9, 77.8, 77.4, 77.1, 74.6, 74.5, 71.5 , 71.2, 71.0, 50.5, 44.1, 40.0, 36.7, 33.4, 28.3, 25.8, 17.5, 16.9, 14.8
(8) Solubility: Soluble in methanol, dimethyl sulfoxide (DMSO) and chloroform. Insoluble in water.

化合物(I−C)の構造式及び理化学的性質は以下のとおりである:
(1)物質の色 :赤色
(2)分子量 :706
(3)分子式 :C37H38O14
(4)質量分析 :ESI-MS(negative mode) 実測値 705.2
(5)紫外線吸収スペクトル(アセトニトリル中) λmax 218, 316, 425nm
(6)H NMR(重クロロホルム中で測定、600MHz)
δppm 12.20 (brs, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.67 (dd, J = 3.4, 10.3 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 6.05 (d, J = 10.3 Hz, 1H), 5.57 (d, J = 3.4 Hz, 1H), 5.17 (d, J = 2.8 Hz, 1H), 4.94 (dd, J = 2.1, 11.0 Hz, 1H), 4.74 (q, J = 7.6 Hz, 1H), 4.70 (q, J = 7.6 Hz, 1H), 4.55 (brs, 1H), 4.32 (m, 1H), 3.81 (m, 1H), 3.56 (brs, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 3.21 (dd, J = 3.4, 13.8 Hz, 1H), 2.62-2.64 (m, 2H), 2.54 (d, J = 13.8 Hz, 1H), 2.45 (m, 1H), 2.45 (dd, J = 2.8, 15.8 Hz, 1H), 1.80 (d, J = 15.8 Hz, 1H), 1.46 (s, 3H), 1.42 (d, J = 6.9 Hz, 3H), 1.38 (m, 1H), 1.38 (d, J = 6.2 Hz, 3H), 1.36 (d, J = 7.6 Hz, 3H)
(7)13C NMR(重クロロホルム中で測定、125MHz)
δppm 208.4, 208.4, 197.4, 188.8, 182.8, 158.5, 146.0, 143.4, 139.3, 139.1, 138.5, 134.3, 131.1, 128.3, 120.4, 117.9, 114.6, 92.0, 89.3, 83.3, 79.9, 78.4, 77.1, 75.2, 75.1, 72.1, 71.8, 71.3, 69.9, 50.8, 43.2, 40.6, 37.3, 27.1, 18.1, 16.8, 15.7
(8)溶解性 :メタノール、ジメチルスルホキシド(DMSO)、クロロホルムに可溶。水に難溶。
The structural formula and physicochemical properties of the compound (I 0 -C) are as follows:
(1) Material color: Red (2) Molecular weight: 706
(3) Molecular formula: C 37 H 38 O 14
(4) Mass spectrometry: ESI-MS (negative mode) measured value 705.2
(5) UV absorption spectrum (in acetonitrile) λmax 218, 316, 425nm
(6) 1 H NMR (measured in deuterated chloroform, 600 MHz)
δppm 12.20 (brs, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.67 (dd, J = 3.4, 10.3 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 6.05 (d, J = 10.3 Hz, 1H), 5.57 (d, J = 3.4 Hz, 1H), 5.17 (d, J = 2.8 Hz, 1H), 4.94 (dd, J = 2.1, 11.0 Hz, 1H), 4.74 (q, J = 7.6 Hz, 1H), 4.70 (q, J = 7.6 Hz, 1H), 4.55 (brs, 1H) , 4.32 (m, 1H), 3.81 (m, 1H), 3.56 (brs, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 3.21 (dd, J = 3.4, 13.8 Hz, 1H), 2.62-2.64 (m, 2H), 2.54 (d, J = 13.8 Hz, 1H), 2.45 (m, 1H), 2.45 (dd, J = 2.8, 15.8 Hz, 1H), 1.80 (d, J = 15.8 Hz , 1H), 1.46 (s, 3H), 1.42 (d, J = 6.9 Hz, 3H), 1.38 (m, 1H), 1.38 (d, J = 6.2 Hz, 3H), 1.36 (d, J = 7.6 Hz , 3H)
(7) 13 C NMR (measured in deuterated chloroform, 125 MHz)
δppm 208.4, 208.4, 197.4, 188.8, 182.8, 158.5, 146.0, 143.4, 139.3, 139.1, 138.5, 134.3, 131.1, 128.3, 120.4, 117.9, 114.6, 92.0, 89.3, 83.3, 79.9, 78.4, 77.1, 75.2, 75.1 , 72.1, 71.8, 71.3, 69.9, 50.8, 43.2, 40.6, 37.3, 27.1, 18.1, 16.8, 15.7
(8) Solubility: Soluble in methanol, dimethyl sulfoxide (DMSO) and chloroform. Insoluble in water.

化合物(I−D)の構造式及び理化学的性質は以下のとおりである:
(1)物質の色 :赤色
(2)分子量 :822
(3)分子式 :C43H50O16
(4)質量分析 :ESI-MS(negative mode) 実測値 821.3
(5)紫外線吸収スペクトル(アセトニトリル中) λmax 219, 316, 429nm
(6)H NMR(重クロロホルム中で測定、600MHz)
δppm 12.30 (brs, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.87 (dd, J = 3.6, 10.1 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 6.04 (d, J = 10.1 Hz, 1H), 5.40 (t, J = 6.3 Hz, 1H), 5.25 (d, J = 3.6 Hz, 1H), 4.97 (brs, 1H), 4.97 (brs, 1H), 4.86 (dd, J = 1.4, 11.3 Hz, 1H), 4.58 (brs, 1H), 4.55 (q, J = 6.7 Hz, 1H), 4.51 (q, J = 6.6 Hz, 1H), 4.22 (m, 1H), 3.95 (brs, 1H), 3.79 (m, 1H), 3.70 (brs, 1H), 3.54 (m, 1H), 3.20 (dd, J = 3.0, 13.1 Hz, 1H), 3.04 (t, J = 8.4 Hz, 1H), 2.51 (d, J = 13.1 Hz, 1H), 2.50 (m, 1H), 2.36-2.38 (m, 2H), 2.35 (dd, J = 3.0, 15.2 Hz, 1H), 2.29 (m, 1H), 2.09 (m, 1H), 2.08 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 1.79 (d, J = 15.2 Hz, 1H), 1.67 (m, 1H), 1.44 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.36 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H)
(7)13C NMR(重クロロホルム中で測定、125MHz)
δppm 210.9, 204.5, 197.0, 188.2, 182.2, 158.1, 145.3, 142.8, 138.2, 138.1, 138.0, 133.7, 130.4, 127.5, 119.1, 117.4, 113.9, 98.9, 95.8, 92.8, 88.4, 82.5, 79.8, 76.7, 75.6, 73.9, 72.0, 70.8, 70.5, 70.2, 67.3, 50.5, 44.1, 38.2, 33.4, 28.3, 25.8, 24.6, 23.8, 18.5, 16.5, 14.8, 14.6
(8)溶解性 :メタノール、ジメチルスルホキシド(DMSO)、クロロホルムに可溶。水に難溶。
The structural formula and physicochemical properties of the compound (I 0 -D) are as follows:
(1) Material color: Red (2) Molecular weight: 822
(3) Molecular formula: C 43 H 50 O 16
(4) Mass spectrometry: ESI-MS (negative mode) measured value 821.3
(5) UV absorption spectrum (in acetonitrile) λmax 219, 316, 429nm
(6) 1 H NMR (measured in deuterated chloroform, 600 MHz)
δppm 12.30 (brs, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.87 (dd, J = 3.6, 10.1 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 6.04 (d, J = 10.1 Hz, 1H), 5.40 (t, J = 6.3 Hz, 1H), 5.25 (d, J = 3.6 Hz, 1H), 4.97 (brs, 1H), 4.97 (brs, 1H), 4.86 (dd, J = 1.4, 11.3 Hz, 1H), 4.58 (brs, 1H), 4.55 (q, J = 6.7 Hz, 1H), 4.51 (q, J = 6.6 Hz, 1H), 4.22 (m, 1H), 3.95 (brs, 1H), 3.79 (m, 1H), 3.70 (brs, 1H), 3.54 (m, 1H), 3.20 (dd, J = 3.0, 13.1 Hz, 1H), 3.04 (t, J = 8.4 Hz, 1H), 2.51 (d, J = 13.1 Hz, 1H), 2.50 (m, 1H), 2.36-2.38 (m , 2H), 2.35 (dd, J = 3.0, 15.2 Hz, 1H), 2.29 (m, 1H), 2.09 (m, 1H), 2.08 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 1.79 (d, J = 15.2 Hz, 1H), 1.67 (m, 1H), 1.44 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.36 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H)
(7) 13 C NMR (measured in deuterated chloroform, 125 MHz)
δppm 210.9, 204.5, 197.0, 188.2, 182.2, 158.1, 145.3, 142.8, 138.2, 138.1, 138.0, 133.7, 130.4, 127.5, 119.1, 117.4, 113.9, 98.9, 95.8, 92.8, 88.4, 82.5, 79.8, 76.7, 75.6 , 73.9, 72.0, 70.8, 70.5, 70.2, 67.3, 50.5, 44.1, 38.2, 33.4, 28.3, 25.8, 24.6, 23.8, 18.5, 16.5, 14.8, 14.6
(8) Solubility: Soluble in methanol, dimethyl sulfoxide (DMSO) and chloroform. Insoluble in water.

上記化合物(I−E)(化合物(I−2))の構造式及び理化学的性質は以下のとおりである:
(1)物質の色 :赤色
(2)分子量 :820
(3)分子式 :C43H48O16
(4)質量分析 :ESI-MS(negative mode) 実測値 819.4
(5)紫外線吸収スペクトル(アセトニトリル中) λmax:218, 317, 428nm
(6)比旋光度[α]D +84(c = 0.2、メタノール、25℃)
なお、化合物(I−2)の加水分解物アグリコンの比旋光度[α]Dは、+119(c = 0.07、メタノール、25℃)であった。
(7)H NMR(重クロロホルム中で測定、600MHz)
δppm 12.30 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.59 (d, J= 7.5 Hz, 1H), 6.86 (dd, J = 3.4, 10.3 Hz, 1H), 6.67 (dd, J = 4.1, 10.3 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 6.09 (d, J = 10.3 Hz, 1H), 6.04 (d, J = 10.3 Hz, 1H), 5.57 (d, J = 4.1 Hz, 1H), 5.24 (d, J = 3.4 Hz, 1H), 4.97 (brs, 1H), 4.93 (brs, 1H) 4.83 (dd, J = 1.4, 10.3 Hz, 1H), 4.71 (q, J = 6.2 Hz, 1H), 4.57 (s, 1H), 4.55 (d, J = 6.9 Hz, 1H), 4.22 (dq, J = 1.5, 6.8 Hz, 1H), 3.79 (m, 1H), 3.69 (brs, 1H), 3.54 (m, 1H), 3.20 (dd, J = 3.4, 13.0 Hz, 1H), 3.04 (m, 1H), 2.53 (d, J = 13.0 Hz, 1H), 2.49 (ddd, J= 1.4, 5.2, 13.1 Hz, 1H), 2.44 (dd, J = 3.4, 15.1 Hz, 1H), 2.10 (m, 1H), 2.08 (m, 1H), 1.93 (m, 1H), 1.80 (d, J = 15.1 Hz, 1H), 1.68 (m, 1H), 1.45 (s, 3H), 1.41 (d, J = 6.9 Hz, 3H), 1.37 (d, J = 6.2 Hz, 3H), 1.36 (dd, J = 5.2, 13.1 Hz, 1H), 1.34 (d, J = 6.2 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H)
(8)13C NMR(重クロロホルム中で測定、125MHz)
δppm 203.6, 196.3, 196.1, 187.6, 181.8, 157.6, 144.8, 142.4, 142.2, 138.2, 138.1, 138.0, 133.2, 129.9, 127.1, 127.0, 119.3, 116.8, 113.4, 98.9, 94.8, 88.4, 88.2, 82.3, 78.8, 76.7, 75.6, 74.0, 70.9, 70.5, 70.2, 70.1, 67.3, 49.7, 42.1, 38.2, 26.0, 24.6, 23.8, 18.0, 16.5, 14.7, 14.6
(9)溶解性 :メタノール、ジメチルスルホキシド(DMSO)、クロロホルムに可溶。水に難溶。
The structural formula and physicochemical properties of the compound (I 0 -E) (compound (I-2)) are as follows:
(1) Substance color: Red (2) Molecular weight: 820
(3) Molecular formula: C 43 H 48 O 16
(4) Mass spectrometry: ESI-MS (negative mode) measured value 819.4
(5) UV absorption spectrum (in acetonitrile) λmax: 218, 317, 428nm
(6) Specific rotation [α] D +84 (c = 0.2, methanol, 25 ° C)
The specific rotation [α] D of the hydrolyzate aglycone of compound (I-2) was +119 (c = 0.07, methanol, 25 ° C.).
(7) 1 H NMR (measured in deuterated chloroform, 600 MHz)
δppm 12.30 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 6.86 (dd, J = 3.4, 10.3 Hz, 1H), 6.67 (dd, J = 4.1, 10.3 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 6.09 (d, J = 10.3 Hz, 1H), 6.04 (d, J = 10.3 Hz, 1H), 5.57 (d, J = 4.1 Hz, 1H), 5.24 (d, J = 3.4 Hz, 1H), 4.97 (brs, 1H), 4.93 (brs, 1H) 4.83 (dd, J = 1.4, 10.3 Hz, 1H), 4.71 (q , J = 6.2 Hz, 1H), 4.57 (s, 1H), 4.55 (d, J = 6.9 Hz, 1H), 4.22 (dq, J = 1.5, 6.8 Hz, 1H), 3.79 (m, 1H), 3.69 (brs, 1H), 3.54 (m, 1H), 3.20 (dd, J = 3.4, 13.0 Hz, 1H), 3.04 (m, 1H), 2.53 (d, J = 13.0 Hz, 1H), 2.49 (ddd, J = 1.4, 5.2, 13.1 Hz, 1H), 2.44 (dd, J = 3.4, 15.1 Hz, 1H), 2.10 (m, 1H), 2.08 (m, 1H), 1.93 (m, 1H), 1.80 (d , J = 15.1 Hz, 1H), 1.68 (m, 1H), 1.45 (s, 3H), 1.41 (d, J = 6.9 Hz, 3H), 1.37 (d, J = 6.2 Hz, 3H), 1.36 (dd , J = 5.2, 13.1 Hz, 1H), 1.34 (d, J = 6.2 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H)
(8) 13 C NMR (measured in deuterated chloroform, 125 MHz)
δppm 203.6, 196.3, 196.1, 187.6, 181.8, 157.6, 144.8, 142.4, 142.2, 138.2, 138.1, 138.0, 133.2, 129.9, 127.1, 127.0, 119.3, 116.8, 113.4, 98.9, 94.8, 88.4, 88.2, 82.3, 78.8 , 76.7, 75.6, 74.0, 70.9, 70.5, 70.2, 70.1, 67.3, 49.7, 42.1, 38.2, 26.0, 24.6, 23.8, 18.0, 16.5, 14.7, 14.6
(9) Solubility: Soluble in methanol, dimethyl sulfoxide (DMSO) and chloroform. Insoluble in water.

2.本発明の化合物の製造
2.1.式(I)で表される化合物の製造
本発明の式(I)で表される化合物は、微生物を培地に培養し、培養物中に該化合物を生成蓄積させ、該培養物から該化合物を採取することにより製造することができる。
2. Production of compounds of the invention 2.1. Formula (I 0) compound represented by the manufacture invention of the compound represented by formula (I 0), the microorganism was cultured in the medium, the compound is produced and accumulated in the culture, said from the culture It can be produced by collecting the compound.

(1)微生物
本発明の製造方法において用いることのできる微生物としては、ストレプトマイセス(Streptomyces)属に属し、かつ上記式(I)で表される化合物を生産することが可能な微生物であれば特に限定されない。そのような微生物としては、例えば、ストレプトマイセス・スピーシーズTK08046株、及び該菌株に由来する変異株、あるいは該菌株の類似菌株を挙げることができる。なお、ストレプトマイセス・スピーシーズTK08046株は、受領番号NITE AP−1138で、平成23年8月30日(2011年8月30日)に、独立行政法人製品評価技術基盤機構特許微生物寄託センター(千葉県木更津市かずさ鎌足2−5−8)に受領され、受託番号NITE P−1138で国内寄託された。また、平成24年10月2日(2012年10月2日)にブダペスト条約に基づく国際寄託へ移管した(受託番号NITE BP−1138)。この菌株は、上記(I)の化合物を製造することができる。
(1) Microorganisms Microorganisms that can be used in the production method of the present invention are microorganisms that belong to the genus Streptomyces and that can produce a compound represented by the above formula (I 0 ). If it does not specifically limit. Examples of such microorganisms include Streptomyces sp. TK08046, mutants derived from the strain, and similar strains of the strain. The Streptomyces sp. TK08046 strain was received at NITE AP-1138 on August 30, 2011 (August 30, 2011). 2-5-8, Kazusa Kamashitsu, Kisarazu Prefecture, and deposited in Japan under the deposit number NITE P-1138. In addition, it was transferred to an international deposit based on the Budapest Treaty on October 2, 2012 (October 2, 2012) (Accession Number NITE BP-1138). This strain can produce the above compound (I 0 ).

ここでいう「変異株」は任意の適当な変異原を用いた変異誘発処理により得られたものであり、「変異原」なる語は、その広義において、例えば変異原効果を有する薬剤のみならずUV照射のごとき変異原効果を有する処理をも含むものと理解すべきである。適当な変異原の例としてエチルメタンスルホネート、UV照射、N−メチル−N’−ニトロ−N−ニトロソグアニジン、ブロモウラシルのようなヌクレオチド塩基類似体及びアクリジン類が挙げられるが、他の任意の効果的な変異原もまた使用され得る。   The “mutant strain” here is obtained by mutagenesis treatment using any appropriate mutagen, and the term “mutagen” in the broad sense includes not only a drug having a mutagenic effect, for example. It should be understood to include treatments having a mutagenic effect, such as UV irradiation. Examples of suitable mutagens include ethyl methanesulfonate, UV irradiation, N-methyl-N′-nitro-N-nitrosoguanidine, nucleotide base analogs such as bromouracil and acridines, but any other effect A typical mutagen can also be used.

ここでいう「類似菌株」としては、ストレプトマイセス・スピーシーズTK08046株の16S rDNA遺伝子の塩基配列(配列番号1に示す)と95%以上相同な塩基配列で表される16S rDNA遺伝子を持つ菌株を挙げることができる。16S rDNA遺伝子の相同性は95%以上であればよいが、97%以上であることが好ましく、98%以上であることがさらに好ましく、100%相同であることが最も好ましい。   As used herein, the term “similar strain” refers to a strain having a 16S rDNA gene represented by a base sequence of 95% or more homologous to the 16S rDNA gene base sequence (shown in SEQ ID NO: 1) of Streptomyces sp. TK08046. Can be mentioned. The homology of the 16S rDNA gene may be 95% or more, preferably 97% or more, more preferably 98% or more, and most preferably 100% homology.

ストレプトマイセス・スピーシーズTK08046株の16S rDNAの塩基配列決定のため、プライマーとして真正細菌16S rDNAのほぼ全長を増幅することの出来る10F、686F、800Rおよび1541Rのプライマーセットを用い、PCRを行った。決定した1516塩基の配列を用いて、BLAST検索を行った結果、相同性の高い上位30位まではストレプトマイセス・スピーシーズまたは属未定の放線菌であり、いずれも98%以上の相同性であったことから、本菌株をストレプトマイセス・スピーシーズに分類した。   In order to determine the base sequence of 16S rDNA of Streptomyces sp. TK08046, PCR was carried out using 10F, 686F, 800R and 1541R primer sets capable of amplifying almost the full length of eubacterial 16S rDNA as primers. As a result of BLAST search using the determined 1516-base sequence, the top 30 highly homologous species were Streptomyces species or genus unknown actinomycetes, both of which were 98% or more homologous. Therefore, this strain was classified as Streptomyces species.

ストレプトマイセス・スピーシーズTK08046株の細菌学的性質については以下の通りである。
1) 細胞の形:菌糸を形成する。
2) 胞子の有無 :有り。
3) スターチカゼイン培地 :良好に生育,コロニーは円形,台状,菌糸状,全体的に褐色。
4) スターチカゼイン液体培養 :良好に生育。
5) デンプンの加水分解 :分解する。
6) 色素の生成 :寒天培地、液体培地で暗褐色の色素を生産。
7) 生育の範囲(pH):pH6〜9
The bacteriological properties of Streptomyces sp. TK08046 are as follows.
1) Cell shape: forming hyphae.
2) Presence or absence of spores: Yes.
3) Starch casein medium: Grows well, colonies are round, trapezoidal, mycelium, and brown overall.
4) Starch casein liquid culture: Grows well.
5) Starch hydrolysis: Decomposes.
6) Production of pigment: Dark brown pigment is produced on agar and liquid media.
7) Growth range (pH): pH 6-9

(2)微生物の培養
本発明における微生物の培養は、通常の微生物の培養方法が用いられる。培地としては、資化可能な炭素源、窒素源、無機物及び必要な生育・生産促進物質を適宜含有する培地であれば、合成培地又は天然培地のいずれでも使用可能である。炭素源としては、グルコース、澱粉、デキストリン、マンノース、フラクトース、シュークロース、ラクトース、キシロース、アラビノース、マンニトール、糖蜜などを単独又は組み合わせて用いられる。さらに、必要に応じて炭化水素、アルコール類、有機酸、アミノ酸(トリプトファンなど)なども用いられる。窒素源としては塩化アンモニウム、硫酸アンモニウム、硝酸アンモニウム、硝酸ナトリウム、尿素、ペプトン、肉エキス、酵母エキス、乾燥酵母、コーン・スチープ・リカー、大豆粉、綿実かす、カザミノ酸などが単独又は組み合わせて用いられる。そのほか、必要に応じて食塩、塩化カリウム、硫酸マグネシウム、炭酸カルシウム、リン酸二水素カリウム、リン酸水素二カリウム、硫酸第一鉄、塩化カルシウム、硫酸マンガン、硫酸亜鉛などの無機塩類を加える。さらに使用する微生物の生育や本発明の化合物の生産を促進する微量成分を適当に添加することができ、そのような成分は当業者であれば適当なものを選択することができる。
(2) Microbial culture In the present invention, a normal microorganism culture method is used for the culture of the microorganism. As the medium, any of a synthetic medium or a natural medium can be used as long as it contains an assimilated carbon source, nitrogen source, inorganic substance, and necessary growth / production promoting substances as appropriate. As the carbon source, glucose, starch, dextrin, mannose, fructose, sucrose, lactose, xylose, arabinose, mannitol, molasses and the like are used alone or in combination. Furthermore, hydrocarbons, alcohols, organic acids, amino acids (such as tryptophan) and the like are also used as necessary. As the nitrogen source, ammonium chloride, ammonium sulfate, ammonium nitrate, sodium nitrate, urea, peptone, meat extract, yeast extract, dry yeast, corn steep liquor, soybean flour, cottonseed meal, casamino acid, etc. are used alone or in combination. . In addition, inorganic salts such as sodium chloride, potassium chloride, magnesium sulfate, calcium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, ferrous sulfate, calcium chloride, manganese sulfate, and zinc sulfate are added as necessary. Furthermore, trace components that promote the growth of the microorganisms to be used and the production of the compounds of the present invention can be appropriately added, and such components can be appropriately selected by those skilled in the art.

培養法としては、液体培養が適しているが、これに限定されるものではない。培養温度は、25〜37℃が適当であり、培養中の培地のpHは7〜9に維持することが望ましく、震盪速度が30〜120rpmで回転又は往復震盪培養することが望ましい。液体培養で通常5〜14日間培養を行うと、目的化合物が培養液中ならびに菌体中に生成蓄積される。培養物中の生成量が最大に達した時に培養を停止する。   As a culture method, liquid culture is suitable, but is not limited thereto. The culture temperature is suitably 25 to 37 ° C., the pH of the medium during the culture is desirably maintained at 7 to 9, and it is desirable to carry out the rotation or reciprocal shaking culture at a shaking speed of 30 to 120 rpm. When culturing is usually performed for 5 to 14 days in liquid culture, the target compound is produced and accumulated in the culture solution and in the cells. The culture is stopped when the production amount in the culture reaches the maximum.

(3)化合物の単離・精製
培養物から本発明の化合物を単離・精製するには、微生物代謝生産物をその培養物から単離・精製するために常用される方法に従って行われる。ここで、「培養物」とは、培養上清、培養菌体、又は菌体の破砕物のいずれをも意味するものである。例えば培養物を濾過や遠心分離により培養瀘液と菌体に分け、濾液を酢酸エチルなど有機溶媒で抽出する。また培養濾液は酢酸エチル、クロロホルムなどで抽出する。ついで、抽出液を濃縮し、カラムクロマトグラフィー、分取薄層クロマトグラフィー、高速液体クロマトグラフィーなどにより精製を行い、本発明の化合物を得る。得られた化合物は、NMR解析などの通常の化学的手法により、上記「1.本発明の化合物の性質」に記載した性質を示すか否かを調べることにより、本発明の化合物であることを確認することができる。
(3) Isolation / Purification of Compound Isolation / purification of the compound of the present invention from a culture is carried out according to a method commonly used for isolating / purifying a microbial metabolic product from the culture. Here, “culture” means any of culture supernatant, cultured cells, or disrupted cells. For example, the culture is separated into culture broth and cells by filtration or centrifugation, and the filtrate is extracted with an organic solvent such as ethyl acetate. The culture filtrate is extracted with ethyl acetate, chloroform or the like. Subsequently, the extract is concentrated and purified by column chromatography, preparative thin layer chromatography, high performance liquid chromatography or the like to obtain the compound of the present invention. The obtained compound is determined to be the compound of the present invention by examining whether or not it exhibits the properties described in “1. Properties of the compound of the present invention” by a usual chemical method such as NMR analysis. Can be confirmed.

なお、培養、精製操作中の本発明の化合物の動向は、フォトダイオードアレイ検出器付き高速液体クロマトグラフィーにより、紫外線吸収を指標として追跡することができる。   In addition, the trend of the compound of the present invention during culturing and purification operations can be traced using ultraviolet absorption as an index by high performance liquid chromatography with a photodiode array detector.

3.本発明の化合物の用途
本発明の化合物は、下記の実施例に示すように、カビ類、特に卵菌類への発育阻害活性が強いので、抗カビ剤として利用することができる。本発明の化合物を有効成分として含む抗カビ剤は、例えば、魚類のカビ病、例えば、ウナギの綿かぶり病、ギンザケ、ニジマス等のミズカビ病、サケ科魚類稚魚の内臓真菌症、ペヘレイのミズカビ病、アユの真菌性肉芽腫症等の予防薬又は治療薬、好ましくは魚用の抗ミズカビ剤(ミズカビ予防薬又は治療薬)等として利用することができる。また、卵菌類を起因生物とする植物疫病の防除剤成分として有用である。
3. Use of the Compound of the Present Invention As shown in the following examples, the compound of the present invention has a strong growth inhibitory activity against molds, particularly oomycetes, and therefore can be used as an antifungal agent. Antifungal agents containing the compound of the present invention as an active ingredient are, for example, fish mold diseases such as eel cotton scab, coho salmon, rainbow trout scab mold disease, visceral mycosis of salmonid fish, pheley scab mold disease It can be used as a preventive or therapeutic agent for fungus granulomatosis of sweetfish, preferably as an anti-smoldering agent (fish preventive or therapeutic agent) for fish. Moreover, it is useful as a control agent component of a plant plague caused by oomycetes.

本発明の化合物を魚類のカビ病の予防薬又は治療薬として使用するには、例えば、本発明の化合物を魚類の試料に混合するか、魚類の養殖水槽に混合するか、又は魚類の養殖水槽の使用砂に混合すればよい。あるいは、本発明の化合物を0.001〜0.1重量%程度含む水又は海水中に魚類又はその卵を浸漬させる、本発明の化合物を0.001〜0.1重量%程度含む懸濁液を魚類の体又は卵全体に噴霧する、又は本発明の化合物を0.001〜0.1重量%程度含む懸濁液を魚類の静脈又は腹腔内に注射器を用いて接種することも可能である。   In order to use the compound of the present invention as a prophylactic or therapeutic agent for fish mold disease, for example, the compound of the present invention is mixed with a fish sample, mixed with a fish culture tank, or a fish culture tank. You can mix it with the used sand. Alternatively, a suspension containing about 0.001 to 0.1% by weight of the compound of the present invention in which fish or an egg thereof is immersed in water or seawater containing about 0.001 to 0.1% by weight of the compound of the present invention. Can be sprayed on the whole body or egg of a fish, or a suspension containing about 0.001 to 0.1% by weight of the compound of the present invention can be inoculated into a vein or abdominal cavity of a fish using a syringe. .

以下に本発明を実施例により具体的に説明する。ただし、本発明は実施例によりその技術的範囲が限定されるものではない。   Hereinafter, the present invention will be described specifically by way of examples. However, the technical scope of the present invention is not limited by the examples.

式(I )の化合物の製造
式(I)の化合物の生産菌としてストレプトマイセス・スピーシーズTK08046株を用いた。該菌株を、200mLのスターチカゼイン培地(スターチ 1.0%、カゼイン 0.03%、NaCl 0.2%、K2HPO4 0.2%、MgSO4 0.005%、CaCO3 0.002%、FeSO4・7H2O 0.001% (W/V)、pH 7.2)を入れた500mLのバッフル付き三角フラスコ中で、30℃にて5日間回転振盪(100rpm)培養し、次に行う大量培養の種菌とした。この種菌培養物を600mLのスターチカゼイン培地の入った2Lの坂口フラスコ3本(計1.8L)に10mLずつ植菌し、30℃、7日間、往復震盪(110rpm)培養した。培養中、培地のpHは特に制御しなかった。
Using Streptomyces sp TK08046 strain as producing bacteria of the compound of preparation formula of the compound of formula (I 0) (I 0) . The strain was added to 200 mL starch casein medium (starch 1.0%, casein 0.03%, NaCl 0.2%, K 2 HPO 4 0.2%, MgSO 4 0.005%, CaCO 3 0.002%, FeSO 4 · 7H 2 O 0.001% (W / In a 500 mL baffled Erlenmeyer flask containing V) and pH 7.2), cultivation was carried out at 30 ° C. for 5 days by rotating and shaking (100 rpm), and used as an inoculum for the next large-scale culture. 10 mL of this inoculum culture was inoculated into three 2 L Sakaguchi flasks (1.8 L in total) containing 600 mL starch casein medium, and cultured at 30 ° C. for 7 days with reciprocal shaking (110 rpm). During the culture, the pH of the medium was not particularly controlled.

このようにして得られた培養液1.8Lをろ過し、菌体とろ液に分離した。ろ液は等量の酢酸エチルで3回抽出した。得られた抽出物をODSシリカゲルカラムクロマトグラフィーにて精製した。ワコーゲル50C18(和光純薬)を担体として用い、移動層として、まず、10%、30%、50%、70%アセトニトリル水で、最後に100%アセトニトリルにて溶出した。30〜100%アセトニトリル水にて溶出した画分に抗卵菌活性が認められた。   1.8 L of the culture solution thus obtained was filtered and separated into cells and filtrate. The filtrate was extracted 3 times with an equal volume of ethyl acetate. The obtained extract was purified by ODS silica gel column chromatography. Wakogel 50C18 (Wako Pure Chemical Industries, Ltd.) was used as a carrier, and the mobile layer was first eluted with 10%, 30%, 50%, 70% acetonitrile water and finally with 100% acetonitrile. Anti-octomy activity was observed in the fraction eluted with 30-100% acetonitrile water.

次に、それら画分を高速液体クロマトグラフィー(カラム:コスモシル5C18ARII(直径10mm、長さ250mm)、移動相:60%アセトニトリル水、流速3mL/min、検出波長220nm)にて精製した。このような培養とその培養物から、培養物計1.8Lから本発明の化合物(I−1)を3.1mg、化合物(I−B)を1.1mg、化合物(I−C)を1.9mg、化合物(I−D)を2.7mg、及び化合物(I−2)を8.1mg得た。Next, these fractions were purified by high performance liquid chromatography (column: Cosmocil 5C18ARII (diameter 10 mm, length 250 mm), mobile phase: 60% acetonitrile water, flow rate 3 mL / min, detection wavelength 220 nm). From such a culture and its culture, the compound (I-1) of the present invention is 3.1 mg, the compound (I 0 -B) is 1.1 mg, and the compound (I 0 -C) is 1.8 L in total. 1.9 mg, Compound (I 0 -D) 2.7 mg, and Compound (I-2) 8.1 mg.

上記化合物(I−1)、(I−B)、(I−C)、(I−D)及び(I−2)について、各種微生物に対する活性を測定し、化合物(I−1)及び(I−2)についてはさらに植物プランクトン(緑藻)及び動物プランクトン(ミジンコ)に対する活性を測定した。比較のために、市販のミズカビ病防止薬剤「パイセス」(商品名、ノベルティスアニマルヘルス株式会社製)の活性も測定した。The above compound (I-1), (I 0 -B), (I 0 -C), the (I 0 -D) and (I-2), and measuring the activity against various microorganisms, compound (I-1) For (I-2), the activity against phytoplankton (green algae) and zooplankton (daphnia) was further measured. For comparison, the activity of a commercially available drug for preventing mold fungus "Piesse" (trade name, manufactured by Novelty Animal Health Co., Ltd.) was also measured.

抗菌活性の測定
真核微生物に対する活性は、96穴マイクロプレートを用いて以下のようにして測定した。化合物(I−1)、(I−B)、(I−C)、(I−D)又は(I−2)は8%メタノール水に懸濁し、4000、2000、1000、500、250、125、62.5、32、16、8又は4μg/mLの試料懸濁液を調製した。また、パイセスは水で希釈して、上記各種濃度のパイセス水溶液を調製した。96穴マイクロプレートの各ウェルに各種濃度の試験液50μl、滅菌した4倍濃縮液体培地50μl、予め準備した被検生物の胞子懸濁液または菌懸濁液100μlを分注した。実験は2連で行い、被検生物に応じた温度で一定時間培養後に、微生物の生育を倒立顕微鏡で観察し、活性の有無を判断した。被検生物および培養条件は以下の通りである。ミズカビ(Saprolegnia parasitica):GY培地(グルコース1%、酵母エキス0.25%、pH6.5)、18℃、24時間、Phoma sp.:YPD培地(酵母エキス1%、ペプトン2%、グルコース2%、pH6.5)、30℃、30時間、Saccharomyces cerevisiae:サブロー培地(マルトース4%、ペプトン1%、pH 6.0)、30℃、30時間。
Measurement of antibacterial activity The activity against eukaryotic microorganisms was measured as follows using a 96-well microplate. Compound (I-1), (I 0 -B), (I 0 -C), (I 0 -D) or (I-2) is suspended in 8% methanol water, and 4000, 2000, 1000, 500, Sample suspensions of 250, 125, 62.5, 32, 16, 8 or 4 μg / mL were prepared. Also, the pieces were diluted with water to prepare pieses aqueous solutions having various concentrations described above. Each well of a 96-well microplate was dispensed with 50 μl of various concentrations of the test solution, 50 μl of a sterilized 4 × concentrated liquid medium, and 100 μl of a prepared spore suspension or bacterial suspension. The experiment was performed in duplicate, and after culturing for a certain time at a temperature corresponding to the test organism, the growth of the microorganism was observed with an inverted microscope to determine the presence or absence of activity. Test organisms and culture conditions are as follows. Saprolegnia parasitica: GY medium (glucose 1%, yeast extract 0.25%, pH 6.5), 18 ° C., 24 hours, Phoma sp .: YPD medium (yeast extract 1%, peptone 2%, glucose 2% , PH 6.5), 30 ° C., 30 hours, Saccharomyces cerevisiae: Sabouraud medium (maltose 4%, peptone 1%, pH 6.0), 30 ° C., 30 hours.

また、原核微生物に対する活性は、ペーパーディスク法により被検生物を練り込んだ寒天平板培地上で測定した。Staphylococcus aureus、Bacillus subtilis 又はEscherichia coliを試験管中の滅菌したLB培地(グルコース0.5%、ポリペプトン1%、酵母エキス0.5%、NaCl 0.5%、pH7.2)3mLに植菌して、1晩37℃で培養した。この前培養液を、滅菌したLB寒天培地(寒天1.5%)に1%接種して、検定用寒天平板を作成した。化合物(I−1)又は(I−2)をメタノールに溶解して、1000、500、250、125、62.5、32、16、8、4、2又は1μg/mLの試料溶液を作成し、ペーパーディスク(ADVANTEC、直径8mm、thick)に染み込ませた後、風乾して検定用寒天平板上に置き、37℃で1晩培養した。ペーパーディスク周辺の阻止円の形成を観察し、活性の有無を判断した。   Further, the activity against prokaryotic microorganisms was measured on an agar plate medium in which a test organism was kneaded by the paper disk method. Inoculate Staphylococcus aureus, Bacillus subtilis or Escherichia coli in 3 mL of sterile LB medium (glucose 0.5%, polypeptone 1%, yeast extract 0.5%, NaCl 0.5%, pH 7.2) in a test tube. And incubated overnight at 37 ° C. 1% of this preculture was inoculated into a sterilized LB agar medium (agar 1.5%) to prepare an agar plate for assay. Compound (I-1) or (I-2) is dissolved in methanol to prepare a sample solution of 1000, 500, 250, 125, 62.5, 32, 16, 8, 4, 2, or 1 μg / mL. The sample was soaked in a paper disc (ADVANTEC, diameter 8 mm, thick), air-dried, placed on an assay agar plate, and cultured at 37 ° C. overnight. The formation of a blocking circle around the paper disk was observed to determine the presence or absence of activity.

抗藻類活性試験
96穴マイクロプレートの各ウェルに、対数増殖期の藻類培養液を150μL、8%メタノール水に懸濁した400、200、100、50、25、12.5、又は6.25μg/mLの試料溶液、又は上記各種濃度のパイセス水溶液を50μL加え、インキュベートした後、倒立顕微鏡で細胞の増殖を観察してポジティブコントロールと同等の状態の場合活性ありとした。緑藻であるクロレラ(Chlorella vulgaris)はC培地で培養し、0.987±0.470×10cells/mLの培養液とし、ポジティブコントロールとしてシクロヘキシミド(最終濃度:100μg/mL)を使用し、25℃、30μmol photons/m/sの条件でインキュベートした。
Anti-algal activity test In each well of a 96-well microplate, 400, 200, 100, 50, 25, 12.5, or 6.25 μg / logarithmic growth phase of algal culture was suspended in 150 μL of 8% methanol water. After adding 50 μL of the sample solution of mL or the above-mentioned various aqueous pieces solution and incubating, cell growth was observed with an inverted microscope, and the cells were regarded as active in the same state as the positive control. Chlorella vulgaris, a green alga, is cultured in C medium, used as a culture solution of 0.987 ± 0.470 × 10 7 cells / mL, using cycloheximide (final concentration: 100 μg / mL) as a positive control, 25 Incubation was performed at 0 ° C. and 30 μmol photons / m 2 / s.

ミジンコ(Daphnia pulex)遊泳阻害活性試験
曝気水10mLに対してミジンコが5個体になるように個体数を調整した。ミジンコは発生後24時間以内の個体を用い、曝気水は浄水器を通した水道水を24時間以上曝気したものを用いた。該ミジンコ飼育水に、化合物(I−1)又は(I−2)をメタノールに溶解した試料溶液、又はパイセスを水で希釈したパイセス水溶液を、ミジンコ飼育水中における試料又はパイセスの最終濃度が100、10、1、0.1又は0.01μg/mLとなるように攪拌しながら添加して24時間インキュベート(20℃、17μmol photons/m/s、Light:Dark=16:8)し、遊泳している個体数を測定した。ミジンコ5個体を1群とし、上記の各種最終濃度の試験液について2群用いて実験を行い、得られた結果から、統計ソフトSPSSを用いたプロビット法によりIC50値を算出した。
Daphnia pulex swimming inhibition activity test The number of individuals was adjusted so that there were 5 daphnia per 10 mL aerated water. Daphnia was an individual within 24 hours after the occurrence, and aerated water was aerated tap water passed through a water purifier for more than 24 hours. A sample solution obtained by dissolving the compound (I-1) or (I-2) in methanol or a pieces aqueous solution obtained by diluting pieces with water in the daphnia breeding water has a final concentration of 100 or 100 in the daphnia breeding water, Add with stirring to 10, 1, 0.1 or 0.01 μg / mL and incubate for 24 hours (20 ° C., 17 μmol photons / m 2 / s, Light: Dark = 16: 8), swim The number of individuals is measured. An experiment was performed using five groups of daphnia as one group and two groups of the test solutions having various final concentrations described above, and IC 50 values were calculated from the obtained results by a probit method using statistical software SPSS.

真核微生物への最小発育阻止濃度(MIC)は、以下の通りであった。ミズカビ(Saprolegnia parasitica)に対しては、化合物(I−1)が0.0039μg/mL、化合物(I−B)が8μg/mL、化合物(I−C)が1μg/mL、化合物(I−D)が1μg/mL及び化合物(I−2)が0.0078μg/mLであった。一方、比較に用いたパイセスのミズカビ(Saprolegnia parasitica)へのMICは5.0μg/mLであった。Saccharomyces cerevisiaeに対しては、化合物(I−1)、(I−B)、(I−C)、(I−D)及び(I−2)は、いずれも1000μg/mLでも生育阻害は認められなかった。Phoma sp. へのMICは、化合物(I−1)、(I−B)、(I−C)、(I−D)及び(I−2)のいずれも500μg/mLであった。The minimum inhibitory concentration (MIC) for eukaryotic microorganisms was as follows. For Saprolegnia parasitica, Compound (I-1) is 0.0039 μg / mL, Compound (I 0- B) is 8 μg / mL, Compound (I 0 -C) is 1 μg / mL, Compound (I 0- D) was 1 μg / mL and Compound (I-2) was 0.0078 μg / mL. On the other hand, the MIC for Pisces saprolegnia parasitica used for comparison was 5.0 μg / mL. For Saccharomyces cerevisiae, compounds (I-1), (I 0 -B), (I 0 -C), (I 0 -D) and (I-2) all inhibited growth even at 1000 μg / mL. Was not recognized. The MIC to Phoma sp. Was 500 μg / mL for all of the compounds (I-1), (I 0 -B), (I 0 -C), (I 0 -D) and (I-2). .

原核微生物への最小発育阻止濃度(MIC)は以下の通りであった。Staphylococcus aureusに対しては、化合物(I−1)が31.2μg/mL、化合物(I−B)が250μg/mL、化合物(I−C)が125μg/mL、化合物(I−D)が62.5μg/mL及び化合物(I−2)が16.0μg/mLで寒天培地上阻止円が観察できた。Bacillus subtilisに対しては、化合物(I−1)が62.5μg/mL、化合物(I−B)が250μg/mL、化合物(I−C)が250μg/mL、化合物(I−D)が62.5μg/mL及び化合物(I−2)が8.0μg/mLで寒天培地上阻止円が観察できた。しかし、Escherichia coliに対しては、化合物(I−1)、(I−B)、(I−C)、(I−D)及び(I−2)のいずれも生育阻止円が認められなかった。The minimum inhibitory concentration (MIC) for prokaryotic microorganisms was as follows. For Staphylococcus aureus, Compound (I-1) was 31.2 μg / mL, Compound (I 0 -B) was 250 μg / mL, Compound (I 0 -C) was 125 μg / mL, Compound (I 0 -D) ) Was 62.5 μg / mL and Compound (I-2) was 16.0 μg / mL, and inhibition circles on the agar medium could be observed. For Bacillus subtilis, Compound (I-1) was 62.5 μg / mL, Compound (I 0 -B) was 250 μg / mL, Compound (I 0 -C) was 250 μg / mL, Compound (I 0 -D) ) Was 62.5 μg / mL and Compound (I-2) was 8.0 μg / mL, and inhibition circles on the agar medium could be observed. However, for Escherichia coli, all of the compounds (I-1), (I 0 -B), (I 0 -C), (I 0 -D) and (I-2) have growth inhibition circles. I couldn't.

また、水圏環境生物である緑藻(Chlorella vulgaris)に対しては、化合物(I−1)及び(I−2)ともに100μg/mLでも影響を与えなかったが、比較に用いたパイセスの緑藻(Chlorella vulgaris)へのMICは62.5μg/mLであった。また、節足動物のミジンコ(Daphnia pulex)の50%遊泳阻害濃度は、化合物(I−1)が2.58μg/mLであり、化合物(I−2)が4.48μg/mLであった。比較に用いたパイセスのミジンコの50%遊泳阻害濃度は3.7μg/mLであった。   In addition, the green algae (Chlorella vulgaris), which is an aquatic environmental organism, did not affect both the compounds (I-1) and (I-2) even at 100 μg / mL, but the green algae (Chlorella used for comparison) MIC to vulgaris) was 62.5 μg / mL. Further, the 50% swimming inhibition concentration of arthropod Daphnia pulex was 2.58 μg / mL for Compound (I-1) and 4.48 μg / mL for Compound (I-2). The 50% migratory inhibitory concentration of Pis daphnia used for comparison was 3.7 μg / mL.

これらの結果から、化合物(I−1)、(I−B)、(I−C)、(I−D)及び(I−2)は、ミズカビ(Saprolegnia parasitica)に対する活性が強く、非常に低濃度で抗ミズカビ効果を発揮するが、他の真核微生物及び原核微生物には弱い活性しか示さないことがわかる。よって、化合物(I−1)、(I−B)、(I−C)、(I−D)及び(I−2)は、選択的な抗ミズカビ活性を有していると考えられる。さらに、化合物(I−1)及び(I−2)は、環境生物(生態系)への影響が非常に低いといえる。From these results, the compounds (I-1), (I 0 -B), (I 0 -C), (I 0 -D) and (I-2) have strong activity against Saprolegnia parasitica, It can be seen that although it exhibits an anti-smoldering effect at very low concentrations, it exhibits only weak activity against other eukaryotic and prokaryotic microorganisms. Therefore, it is considered that the compounds (I-1), (I 0 -B), (I 0 -C), (I 0 -D) and (I-2) have selective anti-mycotyl activity. It is done. Furthermore, it can be said that the compounds (I-1) and (I-2) have very low influence on environmental organisms (ecosystems).

NITE BP−1138 NITE BP-1138

Claims (4)

式(I):
Figure 2013061919
(式中、Rは、
Figure 2013061919
を示し、Rは、
Figure 2013061919
を示す。)で表される化合物又はその塩。
Formula (I 0 ):
Figure 2013061919
(Wherein R 1 is
Figure 2013061919
R 2 is
Figure 2013061919
Indicates. Or a salt thereof.
式(I):
Figure 2013061919
(式中、Rは、
Figure 2013061919
又は
Figure 2013061919
を示す。)で表される化合物又はその塩。
Formula (I):
Figure 2013061919
(Wherein R is
Figure 2013061919
Or
Figure 2013061919
Indicates. Or a salt thereof.
請求項1又は2に記載の化合物を生産する能力を有するストレプトマイセス属に属する微生物を培地に培養し、培養物中に該化合物を生成蓄積させ、該化合物を採取することを特徴とする請求項1又は2に記載の化合物の製造法。   A microorganism belonging to the genus Streptomyces having the ability to produce the compound according to claim 1 or 2 is cultured in a medium, the compound is produced and accumulated in the culture, and the compound is collected. Item 3. A method for producing the compound according to Item 1 or 2. 請求項1又は2に記載の化合物を有効成分として含む抗カビ剤。   An antifungal agent comprising the compound according to claim 1 or 2 as an active ingredient.
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JPS61183278A (en) * 1985-02-09 1986-08-15 Microbial Chem Res Found Benz(a)anthraquinone compound
JPS6470482A (en) * 1987-09-10 1989-03-15 Taisho Pharmaceutical Co Ltd Physiologically active substance pi6621
JPH01193284A (en) * 1988-01-29 1989-08-03 Taisho Pharmaceut Co Ltd Physiologically active substance pi-08s
JPH02223525A (en) * 1988-11-16 1990-09-05 Takeda Chem Ind Ltd Arterialization inhibitor
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